Alnylam looks to next RNAi approval, but safety questions linger

Alnylam on Friday released full results from a pivotal Phase 3 study for givosiran, setting the stage for the company to finish a U.S. regulatory application in the coming months and potentially launch what would be the biotech’s second marketed product by early 2020.

The data, set to be presented Saturday at the European Association for the Study of Liver’s annual meeting in Vienna, Austria, show givosiran led to a 74% reduction in the yearly attack rate for patients with acute hepatic porphyria, compared to placebo. Additionally, half of those on the givosiran arm had no attacks for the six-month treatment period, about three times as many as the placebo arm.

Safety results, though, could warrant a close look by the Food and Drug Administration. In the study, roughly one in five patients experienced a serious adverse event compared to 9% on placebo, although most were not judged related to givosiran.

If approved, givosiran would be the first preventive treatment for acute hepatic porphyria, or AHP —​ a family of very rare, genetic diseases. AHP causes episodic, acute neurological attacks that can be life-threatening. Alnylam estimates 5,000 people in the U.S. and Europe would be eligible for givosiran.

Currently, intravenous infusions of hemin are the only approved AHP treatment and are limited to ameliorating attacks after they happen. While some physicians use hemin off-label for prevention, data on its effectiveness is limited, said Akin Akinc, the Massachusetts biotech’s general manager of givosiran, in an interview with BioPharma Dive.

Delivered via a once-monthly subcutaneous injection, givosiran has brought a large improvement for many AHP patients, Akinc said. But safety questions linger, given the higher number of serious adverse events seen in the drug arm of the study.

Three patients had severe adverse events related to givosiran: namely, pyrexia, abnormal liver function and chronic kidney disease. Akinc argued AHP patients are particularly sick, and frequently have prior history of hypertension as well as chronic kidney and liver disease.

To his point, 93 of the 94 patients in the Phase 3 study, dubbed ENVISION, continued onto an open-label extension. ​

“To us, that speaks to the overall tolerability profile,” Akinc said.

Notably, liver enzyme levels greater than three times normal (or baseline) were seen in seven patients on givosiran and only one on placebo. One of those seven givosiran-treated patients discontinued due to an increase in liver enzyme levels more than eight times the upper limit of normal, which triggered a study protocol-stopping rule.

Alnylam noted, however, that this case did not meet Hy’s Law, a general rule regarding the risk of fatal drug-induced liver injury, and was subsequently resolved.

If givosiran were to reach market, commercialization would bring new challenges for Alnylam. Given the disease’s ultra-rare nature, awareness remains low among physicians as well as patients.

“Most physicians aren’t aware of AHP, they don’t think to think of it when they have a patient in front of them that may have the disease,” said Akinc. “That’s a big area of focus for us, is trying to raise awareness.”

Making matters more difficult, AHP symptoms, such as nausea and severe fatigue, overlap with much more common diseases.

Within the next few months, Alnylam plans to finish up givosiran’s rolling application in the U.S. and also submit for regulatory approval in Europe.